Phosphorus, the sixth most abundant element in the human body, is critical for bone mineralization, cellular structure, genetic coding, and energy metabolism. Approximately 1,000 g of phosphorus, constituent in a variety of organic and inorganic forms, is present in an adult human. About 80-90% of the phosphorus is in bone, 10-14% is intracellular, and the remaining 1% is extracellular.
Phosphorus is present in nearly all foods, and absorption of dietary phosphorus from ingesta in the gastrointestinal (GI) tract is very efficient. Normal daily dietary intake varies from 800-1,500 mg of phosphorus. Typically, 70-90% of dietary phosphorus is absorbed, primarily from the jejunum, duodenum, and proximal ileum of the GI tract, although some absorption continues throughout the remainder of the intestinal tract. A small amount of GI excretion occurs.
In the normal adult human, serum phosphorus levels range from 2.5 to 4.5 mg/dL (0.81 to 1.45 mmol phosphorus/L). (Normal serum levels are typically 50% higher in infants and 30% higher in children due to growth hormone effects.) A condition of phosphorus homeostasis is normally maintained in the body of a subject, wherein the amount of phosphorus absorbed from the gastrointestinal tract approximately equals the amount excreted via the kidney. In addition, cellular release of phosphorus is balanced by uptake in other tissues. Hormonal control is provided by parathyroid hormone.
Since the kidney plays a central role in maintaining phosphorus homeostasis, kidney dysfunction is often accompanied by increased phosphorus retention by the body. In early kidney dysfunction, compensatory physiological responses allow for a continued match between urinary phosphorus excretion and phosphorus absorption from the gastrointestinal (GI) tract. With more advanced renal failure, however, elevated serum phosphorus is a predictable co-morbidity.
Hyperphosphatemia is a disease state in which there is an abnormally elevated serum phosphorus (Pi) level in the body. Hyperphosphatemia is a particular problem of chronic kidney disease (CKD) patients who are treated using dialysis. Conventional dialysis fails to reduce levels of phosphorus in the blood, and serum phosphorus levels increase with time. Significant hyperphosphatemia is considered present when serum phosphorus levels are greater than about 5 mg/dL in adults or 7 mg/dL in children or adolescents. [National Kidney Foundation. Am J Kidney Dis 2003; 42 (Suppl 3):S1-S201.]
In patients with CKD, phosphorus retention (as evidenced by abnormally elevated serum phosphorus levels) may contribute to progression of renal failure and is a major factor in the development of secondary hyperparathyroidism, renal osteodystrophy, and soft tissue calcification. [Block G A, Klassen P S, Lazarus J M, Ofsthun N, Lowrie E G, Chertow G. J Am Soc Nephrol 2004 August; 15(8): 2208-2218.] Prevention of phosphorus retention with dietary and pharmacological means is frequently required to prevent or reverse secondary hyperparathyroidism and the morbidities and mortality risks associated with it. [Qunibi W Y. Kidney Int 66 (Suppl 90): S8-S12. Alfrey A C. Kidney Int 66 (Suppl 90): S13-S17.]Phosphorus (Pi) binders which bind dietary phosphorus in the gastrointestinal tract are, therefore, clinical mainstays in restoring phosphorus balance and preventing hyperphosphatemia in the roughly 450,000 end-stage renal disease (ESRD) patients in the United States.
Phosphorus Binders. Phosphorus binders are ingested orally by a subject to bind dietary phosphate and convert it to insoluble phosphate salts, thus preventing its absorption from the GI tract. Phosphorus binding is a chemical reaction between dietary phosphorus and a cation of the binder compound, resulting in the formation of insoluble and hence unabsorbable phosphate compounds; adsorption of phosphorus-containing anions on the surface of binder particles; or a combination of both processes. Two classes of phosphorus binders are known: metal salts and cationic polymers. Known metal salts with phosphate-binding properties are calcium salts, including calcium acetate, calcium carbonate, calcium citrate, calcium alginate, calcium gluconate, calcium lactate, and calcium sulfate; magnesium salts, including magnesium carbonate, and magnesium hydroxide; aluminum salts, including aluminum hydroxide and aluminum carbonate; ferric citrate and ferric acetate; lanthanum salts, including lanthanum carbonate; and zirconium salts. Cationic polymers that exhibit phosphorus binding include high molecular weight polymers having multiple amine substituents, such as, by way of example, a polymer known as sevelamer hydrochloride (marketed as “RenaGel®” by Genzyme, Inc.).
In U.S. Pat. No. 4,889,725 Veltman discloses a means for promoting the neutralization reaction between particulate calcium carbonate and ionized phosphate by adding a material formed by the reaction of particulate calcium carbonate and dilute hydrofluoric acid. The products of this invention are useful in lowering serum phosphorus levels in patients undergoing renal dialysis, and are also useful as antacids.
A common treatment for controlling Pi levels is disclosed in U.S. Pat. No. 4,870,105 to Fordtran, which discloses a calcium acetate phosphorus binder for oral administration to an individual for the purpose of inhibiting gastrointestinal absorption of phosphorus. It further discloses a method of inhibiting gastrointestinal absorption of phosphorus, comprising administering orally the calcium acetate phosphorus binder, preferably close in time to food and beverage consumption. Likewise, U.S. Pat. No. 6,576,665 to Dennett, Jr. et al. discloses a composition for inhibiting gastrointestinal absorption of phosphorus in an individual. The composition includes a quantity of calcium acetate sufficient to bind the phosphorus and having a bulk density of between 0.50 kg/L and 0.80 kg/L and is dimensioned to form a caplet for fitting within a capsule. Further provided is a method for administering the calcium acetate composition. Likewise, U.S. Pat. No. 6,875,445 to Dennett, Jr., et al. discloses a composition for binding phosphorus within the gastrointestinal tract of an individual. The composition includes a quantity of calcium acetate having a specific bulk density sufficient to bind the phosphorus in the gastrointestinal tract of an individual. Further provided is a method for administering the calcium acetate composition.
U.S. Pat. No. 6,160,016 to DeLuca discloses a calcium formate composition for oral administration to an individual for the purpose of inhibiting gastrointestinal absorption of phosphorus. It further discloses a method of inhibiting gastrointestinal absorption of phosphorus, comprising administering orally the composition, preferably close in time to food and beverage consumption. Likewise, U.S. Pat. No. 6,489,361, to DeLuca discloses a calcium formate composition for oral administration to an individual for the purpose of inhibiting gastrointestinal absorption of phosphorus. Further, DeLuca discloses a method of inhibiting gastrointestinal absorption of phosphorus, comprising administering orally the calcium formate composition of his invention, preferably close in time to food and beverage consumption.
U.S. Pat. No. 4,689,322, to Kulbe et al. provides calcium salts or calcium mixed salts of polymeric, anionic carboxylic acids and/or an ester of sulfuric acid, and methods for their preparation and use, discloses a pharmaceutical product which contains at least a calcium salt or a calcium mixed salt of a natural or chemically modified polymeric, anionic carboxylic acid and/or an ester of sulfuric acid, and additive materials and/or carrier materials. There are further disclosed calcium salts, and methods of preparation thereof, comprised of polymannuronic acid, polygalacturonic acid, polyglucuronic acid, polyguluronic acid, the oxidation products of homoglycans, the oxidation products of heteroglycans, or their mixtures, for controlling the levels of phosphorus, calcium and iron in patients with chronic uremia and/or the control of the oxalate and/or phosphate of the blood in kidney stone prophylaxis.
U.S. Pat. No. 6,887,897 to Walsdorf and Alexandrides discloses a calcium glutarate supplement and its use for controlling phosphate retention in patients on dialysis and suffering from renal failure and associated hyperphosphatemia. Therapeutic benefit can be realized by administering a calcium glutarate compound orally to a patient to increase available calcium and contact and bind with ingested phosphorus in the patient's digestive tract, and thereby prevent its intestinal absorption.
The Pi binding properties of magnesium salts have been studied by Fine et al. in acute studies involving normal subjects. [Fine K D, Santa Ana C A, Porter J L, Fordtran J S. Intestinal absorption of magnesium from food and supplements. J Clin Invest 1991; 88: 396-402.] They found a dose-dependent decrease in Pi absorption from ingesta that ranged from 75% Pi absorption with placebo to 28% Pi absorption with 77 mEq magnesium acetate (MgAc) per os. Fine stated that Pi absorption by magnesium acetate was comparable to that of calcium acetate, a current standard of care. However, Fine rejected use of magnesium acetate, because “the risk of hypermagnesemia and diarrhea from MgAc ingestion would likely limit the clinical usefulness of MgAc as a P binder.” [ibid, page 401, column 1, paragraph 4]
Several investigators have evaluated the use of orally administered magnesium (Mg) hydroxide- or carbonate-containing Pi binders in the treatment of ESRD patients undergoing dialysis. Guillot et al., treated nine patients undergoing conventional hemodialysis with oral magnesium hydroxide for three to five weeks. [Guillot A P, Hood V L, Runge C F, Gennari F J. The use of magnesium-containing phosphate binders in patients with end-stage renal disease on maintenance hemodialysis. Nephron 1982; 30:114-117.] Using doses averaging 734 mg of elemental Mg/day and concurrent dialysis with dialysate having Mg concentrations of 1.2 to 1.8 mg/dl, the serum Pi levels fell from a control (no binders) value of 9.0 mg/dL to 8.1 mg/dL as a result of treatment. The mean serum Mg levels were 4.32 mg/dL. Four of nine patients developed diarrhea. In contrast to the Guillot study, Mactier et al. observed no effect of oral choline magnesium trisalicylate (trilisate) on serum Pi levels in either hemodialysis or peritoneal dialysis patients. [Mactier R A, Leung A C T, Henderson I S, and Dobbie J W. Control of hyperphosphatemia in dialysis patients: Comparison of aluminum hydroxide, calcium carbonate, and magnesium trilisate. Dial Transplant 1987; 16: 599-601.] Adverse findings were reported by Oe et al., who studied eighteen patients undergoing conventional hemodialysis who were switched from oral Al((OH)3 to Mg(OH)2. [Oe P L, Lips P, van der Meulen J, de Vries P M J M, van Bronswuk H. Long-term use of magnesium hydroxide as a phosphate binder in patients on hemodialysis. Clin Nephrol 1987; 28: 180-185.] Serum Pi levels rose from 4.3 to 6.1 mg/dL despite an average daily intake of 991 mg of elemental Mg and use of a dialysate lacking Mg. The serum Mg level averaged 4.3 mg/dL during Mg(OH)2 treatment. The potassium levels were significantly higher when patients received Mg(OH)2 compared to the control phase (5.7±0.3 vs. 5.1±0.4 mEq/L). O'Donovan et al. switched 28 patients undergoing conventional hemodialysis from oral Al(OH)3 to oral MgCO3 in combination with a Mg-free dialysate. [O'Donovan R, Baldwin D, Hammer M, Moniz C, Parsons V. Substitution of aluminium salts by magnesium salts in control of dialysis hyperphosphataemia. Lancet 1986; 1: 880-882.] Over the two-year study period, Ca, P, and Mg levels were well controlled and not different from those in the control phase. The amount of elemental Mg used varied between 155 to 465 mg/day. Diarrhea was mild and transient. Similar data were reported by Moriniere et al. [Moriniere P, Vinatier I, Westeel P F. Magnesium hydroxide as a complementary aluminum-free phosphate binder to moderate doses of oral calcium in uraemic patients on chronic haemodialysis. Nephrol Dial Transplant 1988; 3: 651-656.] They also reported severe hyperkalemia as high as 8 mEq/L in many patients, the etiology of which was unclear. More recently, this same group performed a controlled study in which patients were either treated with CaCO3 plus Mg(OH)2 as needed or Mg(OH)2 alone and 1-alpha-hydroxyvitamin D3. [Morniere P, Maurouard C, Boudailliez B, Westeel P, Achard J, Boitte F, El Esper N, Compagnon M, Maurel G, Bouillon R, Pamphile R, Fournier A. Prevention of hyperparathyroidism in patients on maintenance dialysis by intravenous 1-alpha-hydroxyvitamin D3 in association with Mg(OH)2 as sole phosphate binder. Nephron 1992; 60: 154-163.] Neither the combination of oral calcium carbonate/magnesium hydroxide nor magnesium hydroxide alone was effective in suppressing parathyroid hormone (PTH) secretion, and uncontrolled hyperphosphatemia forced a reduction in the dose of 1-alpha-hydroxyvitamin D3. Delmez et al. showed that magnesium carbonate was well-tolerated and controlled Pi and Mg levels when given in conjunction with a dialysate having a Mg concentration of 0.6 mg/dL. [Delmez J A, Kelber J, Norword K Y, Giles K S, Slatopolsky E. Magnesium carbonate as a phosphorus binder: A prospective, controlled, crossover study. Kidney Int 1996; 49: 163-167.] In addition, Delmez showed that oral magnesium carbonate (dose, 465±52 mg/day elemental Mg) allowed a decrease in the amount of elemental calcium ingested from 2.9±0.4 to 1.2±0.2 g/day (P<0.0001). Moreover, the combined treatment allowed an increase in the maximum dose of intravenous calcitriol without causing hypercalcemia.
Recently, Fresenius Medical Care A G & Co. KGaA (Bad Homburg Germany) received regulatory approval from Germany's Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte) for a new phosphate binding agent. The Fresenius drug, called “OsvaRen,” is a phosphate binding agent that is made from a combination of calcium acetate and magnesium carbonate.
U.S. Pat. No. 6,926,912 to Roberts et al. discloses a non-aluminum containing mixed metal compound for pharmaceutical use, which may be a mixed metal hydroxy carbonate containing magnesium and iron, and may have a hydrotalcite structure, preferably a non-aged hydrotalcite structure. Other metals, including calcium, lanthanum and cerium, may also be used. U.S. Pat. No. 4,988,569 to Okazaki et al. discloses a phosphate adsorbent comprising a magnesium oxide-titanium dioxide complex as an active ingredient and a phosphate adsorbent having said complex deposited on active carbon.
Phosphate-binding polymers include sevelamer, which is marketed under the brand name RenaGel® (Genzyme, Waltham Mass.), Oxasorb®, and polymers prepared using the methods disclosed in U.S. Pat. Nos. 5,496,545, 5,667,775, 6,083,495; 6,509,013, 6,726,905, 6,844,372, 6,858,203, and 7,087,223. U.S. Pat. No. 6,132,706 to Hider and Canas-Rodriguez discloses methods of medical treatment for excess phosphate using guanidine-containing polymers. U.S. Pat. Nos. 6,383,518 and 6,697,087, both to Matsuda and Kubota, disclose phosphate-binding polymer preparations. In U.S. Pat. No. 7,014,846 Holmes-Farley et al. disclose phosphate-binding polymers for oral administration.
L-Carnitine. L-(−)-Carnitine is a vitamin-like nutrient that is essential for energy production and fat metabolism in the physiological systems of birds, fish, and mammals and has the structure:

For humans, L-carnitine is supplied to the body through both endogenous synthesis (about 25% of adult daily requirement) and food intake (about 75% of adult daily requirement). Meats, in particular beef and lamb, are the major dietary sources of L-carnitine. (Fruits and vegetables are poor dietary sources of L-carnitine.)
Within the human body, the major sites of L-carnitine biosynthesis are the liver and kidney, and these organs synthesize sufficient L-carnitine for local use and for export to other tissues, including the muscles and heart. Biosynthesis also takes place in the brain and testes. Biosynthesis requires lysine, methionine, vitamin C, iron, vitamin B6, and niacin. Dysfunction of the liver or kidney, such as cirrhosis of the liver or chronic kidney disease, may restrict the biosynthesis of L-carnitine and alter the diet, causing concomitant, deleterious L-carnitine deficiency.
Supplemental L-carnitine is available and has been used to mitigate L-carnitine deficiency. However, conventional L-carnitine compositions exhibit noxious odor and taste, as well as hygroscopicity. After ingestion, supplemental L-carnitine has a bioavailability that ranges between about 3% and about 20% of the administered dose.
L-Carnitine functions as a requisite mediator of acyl transport and accepts acyl groups from a variety of acylCoA derivatives in cells and tissues throughout the body. In humans, the transport activity of L-carnitine is particularly important in working muscle, for example, in the muscles throughout the body and the heart. Both types of tissues are dependent on fatty acid metabolism for energy supply, and L-carnitine mediates the translocation of fatty acyl groups across mitochondrial membranes to the sites of oxidation in the mitochondria. In addition, L-carnitine shuttles short chain fatty acids from inside the mitochondria to the cytosol.
A physiologically adequate concentration of L-carnitine is required to provide nutritional support for producing energy in muscles and heart, for mitochondrial long-chain fatty acid oxidation, buffering of the mitochondrial acyl CoA/CoA couple, scavenging acyl groups, peroxysomal fatty acid oxidation, branched-chain amino acid oxidation, and membrane stabilization.
The kidneys are sites of endogenous synthesis of L-carnitine as well of organs of excretory regulation. Under normal physiological conditions, 90% to 95% of the L-carnitine which undergoes glomerular filtration is subsequently reabsorbed by the renal tubules, with the balance excreted in the urine either as acetyl L-carnitine (the major form) or as L-carnitine. Individuals with chronic kidney disease (CKD) exhibit dysregulation of L-carnitine metabolism concomitant with reduction in glomerular filtration rate and other symptoms of renal failure. As a result, the concentration of free L-carnitine in the blood is lowered and the concentrations of L-carnitine esters in the blood are raised. In addition, progressive damage of the renal parenchyma leads to a loss of renal capacity to synthesize L-carnitine, reducing the intracellular L-carnitine concentration. Moreover, maldigestion, impaired absorption by the small intestine in uremia, and restrictions in dietary protein intake may contribute to an increasing L-carnitine deficiency in CKD patients. Finally, CKD patients who undergo hemodialysis lose L-carnitine during the dialysis procedure in excess of the endogenous synthesizing capacity. All of these factors render individuals with renal disease deficient in L-carnitine.
Because L-carnitine functions as a requisite mediator of acyl transport in the body, an L-carnitine deficiency is a serious physiological disorder. Individuals who suffer from L-carnitine deficiency are afflicted with muscle weakness (myasthenia), accompanied by an accumulation of lipids in specific types of muscle fibers. Severe L-carnitine deficiency may present as myasthenia gravis. Individuals who suffer from systemic L-carnitine deficiency and also secondary L-carnitine deficiency associated with organic acidemias may experience vomiting, stupor, confusion and in severe or prolonged occasions of systemic L-carnitine deficiency accompanied by stressful stimuli, coma in encephalopathic episodes.
It is known that increasing the serum L-carnitine concentration to more normal values provides significant benefit to individuals with renal disease. For example, intravenous administration of L-carnitine has been reported to decrease total cholesterol and LDL cholesterol while significantly increasing HDL cholesterol. [M. Bulla et al., “Dysregulation of carnitine metabolism in renal insufficiency,” pages 177-194 in Carnitine: Pathobiochemical Basics and Clinical Applications, H. Seim and H. Loster, Eds. Ponte Press, Bochum, Germany, 1996] Likewise, Golper et al. have reported that intravenous administration of L-carnitine reduced the serum phosphate concentrations significantly. [T. A. Golper et al. “Multicenter trial of L-carnitine in maintenance hemodialysis patients. II. Clinical and biochemical effects.” Kidney Intl 1990; 38: 912-918] Similarly encouraging observations have been reported with regard to cardiomyopathy, muscular myasthenia, hypotension and arrhythmia in CKD patients undergoing hemodialysis.
The ideal Pi binder should bind most dietary phosphorus in the gastrointestinal tract without producing significant adverse effects. It should also be relatively inexpensive, because most dialysis patients usually consume relatively large daily doses of the binder. Further, if components in the ideal Pi binder are absorbed from the gastrointestinal tract, these moieties should have beneficial physiological activities. Unfortunately, none of the currently used Pi binders fulfill all of these requirements. It would be very useful, therefore to have a Pi binder which binds dietary phosphorus more effectively, thus enabling use of lower doses, which does not have the risks associated with ingestion of conventional Pi binders, and which has pluripotent benefits to the subject. The present invention answers this unmet need.